Eyssen et al. (1972) reported 2 infant brothers with intrahepatic cholestasis and partial atresia of the intrahepatic bile ducts who died at ages 4 and 6 months, respectively. Analysis of bile acids of 1 child showed increased levels ... Eyssen et al. (1972) reported 2 infant brothers with intrahepatic cholestasis and partial atresia of the intrahepatic bile ducts who died at ages 4 and 6 months, respectively. Analysis of bile acids of 1 child showed increased levels of 3-alpha-7-alpha-12-alpha-trihydroxy-5-beta-cholestan-26-oic acid (THCA). Another unrelated female patient also had cholestatic jaundice with increased levels of THCA. Bile acids are normally synthesized in the liver by hydrogenation and hydroxylation of the steroid nucleus of cholesterol, followed by oxidation of the side chain. In certain lower vertebrates, including the Alligator mississippiensis, the side chain of cholesterol is oxidized but not degraded such that THCA is itself a major bile acid. Hanson et al. (1975) noted that the 2 brothers reported by Eyssen et al. (1972) had other congenital anomalies, including frontal bossing, epicanthal folds, and simian creases, perhaps representing another disorder of peroxisomal defect (see, e.g., Zellweger syndrome, 214100; Bove et al., 2000). Hanson et al. (1975) reported 2 sibs with neonatal jaundice, hepatomegaly, and an abnormal bile acid pattern similar to that reported by Eyssen et al. (1972). The extrahepatic biliary system was patent in 1 examined child. Both patients died of cirrhosis of the liver at ages 8 and 23 months, respectively. In both patients, mass spectroscopy confirmed increased levels of THCA which was identical to that found in Alligator mississippiensis. Hanson et al. (1975) postulated a defect in the mitochondrial conversion of THCA to cholic acid that is transmitted in an autosomal recessive pattern. Sequeira et al. (1998) reported an Asian infant, born to doubly consanguineous parents, with Niemann-Pick disease type C (257220) and a defect in peroxisomal beta-oxidation. He was thought to have 2 distinct genetic defects. Steatorrhea and fat-soluble vitamin malabsorption responded well to bile acid therapy. Van Veldhoven et al. (2001) reported a female infant with a mild bleeding disorder that responded to vitamin K administration. Family history was significant for an older brother who died with a diagnosis of 'vitamin K deficiency.' Additional studies of the girl showed increased conjugated bilirubin, abnormal liver enzymes, decreased vitamin E and D, and normal hemoglobin. Liver biopsy showed giant cell neonatal hepatitis with occasional lack of bile ducts. There was no ductal cholestasis, but urine showed increased bile acid secretion consistent with cholestasis. Very-long-chain fatty acids and pristanic acid were normal, suggesting an isolated defect in the degradation of bile acid intermediates. Patient fibroblasts showed a defect in the formation of CO2 from R-pristanic acid compared to controls, suggesting a peroxisomal beta-oxidation defect at the level of 2-methylacyl-CoA racemase. Finally, immunoblot analysis showed decreased levels of the racemase protein compared to controls and to her parents. Setchell et al. (2003) provided follow-up of the patient reported by Van Veldhoven et al. (2001). Liver biopsies showed giant cell transformation, hepatocyte necrosis, and reduced numbers of peroxisomes. Analysis of bile acids in urine, serum, and bile showed high concentrations of THCA similar to that seen in Zellweger syndrome and in the Alligator mississippiensis. The patient showed a good response to oral cholic acid treatment for more than 7 years. Analysis of the urine from the recipient of her deceased brother's liver confirmed the same bile acid synthetic defect.
In an infant with a defect in bile acid synthesis and increased levels of THCA, Setchell et al. (2003) identified a homozygous mutation in the AMACR gene (604489.0001). An earlier-born affected sib, who died at age 6 months, ... In an infant with a defect in bile acid synthesis and increased levels of THCA, Setchell et al. (2003) identified a homozygous mutation in the AMACR gene (604489.0001). An earlier-born affected sib, who died at age 6 months, also had the mutation. In a child with a defect in bile acid synthesis reported by Sequeira et al. (1998), Ferdinandusse et al. (2000) identified a homozygous mutation in the AMACR gene (604489.0002).